Question

Many drugs are very large NON-POLAR molecules that show some bit of motility. And are

difficult for the body to transport from body location to another. Discuss using the drug below

(vitamin B12), how you would go about modifying the drug further to accommodate a more

flexible motility.

CH, CH NH2 -N NH NA NA Nu H2C OH /

Answer 1

Cobalamin (Cbl) is an essential nutrient for mammals, because two of its derivatives, methyl-Cbl and 5′-deoxyadenosyl-Cbl (Ado-Cbl), act as coenzymes for methionine synthase and methyl-malonyl-CoA mutase, respectively (1, 2). Only microorganisms are capable of synthesizing Cbl. Consequently, animals have developed a complex pathway for gastrointestinal absorption, blood transport, and cellular uptake of dietary Cbl or vitamin B12 (cyano-Cbl). Cbl delivery from food to tissues involves three successive transport proteins and their cell-surface receptors (3, 4). Protein-free Cbl is first bound to haptocorrin (HC) in saliva. After proteolysis of HC–Cbl and other protein complexes of dietary Cbl in the duodenum, Cbl binds to intrinsic factor (IF) in the proximal ileum. The IF–Cbl complex enters mucosal cells in the distal ileum by receptor-mediated endocytosis, and Cbl is transferred to transcobalamin II (TC) (5), whose suggested source is the vascular endothelium (5), and which is the only nonglycosylated protein among the transporters. TC–Cbl is released to the plasma and enters cells by endocytosis via a receptor of as-yet-controversial identity (4). After dissociation of the TC–Cbl complex in lysosomes, Cbl is transformed to the coenzymes methyl- and Ado-Cbl in the cytoplasm and in mitochondria, respectively. Approximately one-quarter of Cbl in plasma is bound to TC, whereas the rest circulates bound to plasmatic HC that can enter only hepatocytes. All three proteins carry a single Cbl molecule and show high affinity to the ligand (6) but differ in specificity for Cbl and its analogues produced by microorganisms (7).